HER2 Subtype Offers Clues for Individualizing Breast Cancer Care

One-third of patients previously identified as having HER2-positive breast cancer were found to also have a luminal subtype that was resistant to chemotherapy and trastuzumab but still sensitive to the triplet neoadjuvant regimen of pertuzumab, trastuzumab, and chemotherapy, according to results of the Neoadjuvant Breast Registry Symphony Trial (NBRST) study.

The phase IV registry study, which was presented during the 2015 San Antonio Breast Cancer Symposium in December, showed that 32.5% of patients with HER2-positive breast cancer also had luminal-type disease. In this resistant group, chemotherapy and trastuzumab alone showed a pathological complete response (pCR) rate of just 6% compared with 39% with the addition of pertuzumab (P = .0002), representing a distinct subgroup for tailoring treatment.

In an interview with OncLive, lead study author Peter Beitsch, MD, chief physician, Dallas Surgical Group, discussed the phase IV study, the significance of these findings, and the potential they have on changing clinical practice.

OncLive: Can you discuss the NBRST study?

Beitsch: The NBRST study is a neoadjuvant registry looking at both Mammaprint and BluePrint analyses prior to neoadjuvant chemotherapy, and then seeing how patients respond to that chemotherapy. At the end, they undergo surgery. The primary goal was to relate the Mammaprint and the BluePrint assays to either a pCR or a non-pCR.

What were the findings?

There were several major findings. The most important one is that we reclassified about 25% of the patients in the study. We looked at their functional molecular subtype, which is the way it was initially described with messenger RNA, as compared with the surrogate subtyping, which we do nowadays with immunostaining for ER-positivity and PR-positivity, and FISH testing for HER2.

The second major finding was quite a surprise, actually. We had known for a long time that triple-positive patients, which are patients who are ER+, PR+, and HER2+, respond less to chemotherapy plus trastuzumab than if you are ER-negative and HER2-positive. That group of patients has always done better with pCR, survival, etc.

This has always been a conundrum. In the first part of the study, we were seeing a trend where the triple-positive patients were subtyping into two groups: one that was HER2-driven and one that was of a luminal subtype. When we look at the pCR rates between the two, it was apparent that there was almost no pCR in the luminal subtype, and almost all of the pCR in the triple-positive patients came from the HER2-driven subtype.

However, over the course of the study, the standard of care changed regarding chemotherapy. For HER2-positive patients, it went from chemotherapy plus trastuzumab to chemotherapy plus trastuzumab plus pertuzumab.

Therefore, about 6 months ago, when we were analyzing the data, we saw this trend of a 3% to 4% pCR in the luminal patients, and then it tripled up to an 18% pCR. We thought, “Maybe we’re not as smart as we thought we were.”

Then, we thought that, perhaps, there was indeed a difference between response with trastuzumab and chemotherapy only versus the dual blockade plus chemotherapy. Low and behold, it’s almost like a dividing line. Before receiving pertuzumab, in patients who received chemotherapy and trastuzumab, they demonstrated a 4% pCR. When you add pertuzumab, there was a 40% pCR.

It’s apparent that in the triple-positive patients who are luminal subtype, which is about one-third of all HER2-positive patients, they need not just trastuzumab and chemotherapy; they need trastuzumab, pertuzumab, and chemotherapy to have an improvement in the survival—if you consider pCR to be a surrogate for survival, and I think most people consider that to be the case. We are pretty excited about that.

How could this information impact clinical practice?

Pertuzumab is already approved in the neoadjuvant setting for HER2-positive patients. However, the vast majority of patients don’t get treated in the neoadjuvant setting; they get treated in the adjuvant setting. The cancer has already been removed, the lymph nodes have already been sampled and biopsied, and most of the patients are going to get chemotherapy with trastuzumab.

The problem is, in the patients who are triple-positive and are of the luminal subtype, it is probably not going to help much if you don’t add in pertuzumab. Our study creates an excellent argument to insurance companies to allow for pertuzumab to be given in addition to trastuzumab in the adjuvant setting.